Whole Exome Sequencing Enhanced Imputation Identifies 85 Metabolite Associations in the Alpine CHRIS Cohort

Abstract

Metabolites are intermediates or end products of biochemical processes involved in both health and disease. Here, we take advantage of the well-characterized Cooperative Health Research in South Tyrol (CHRIS) study to perform an exome-wide association study (ExWAS) on absolute concentrations of 175 metabolites in 3294 individuals. To increase power, we imputed the identified variants into an additional 2211 genotyped individuals of CHRIS. In the resulting dataset of 5505 individuals, we identified 85 single-variant genetic associations, of which 39 have not been reported previously. Fifteen associations emerged at ten variants with >5-fold enrichment in CHRIS compared to non-Finnish Europeans reported in the gnomAD database. For example, the CHRIS-enriched ETFDH stop gain variant p.Trp286Ter (rs1235904433-hexanoylcarnitine) and the MCCC2 stop lost variant p.Ter564GlnextTer3 (rs751970792-carnitine) have been found in patients with glutaric acidemia type II and 3-methylcrotonylglycinuria, respectively, but the loci have not been associated with the respective metabolites in a genome-wide association study (GWAS) previously. We further identified three gene-trait associations, where multiple rare variants contribute to the signal. These results not only provide further evidence for previously described associations, but also describe novel genes and mechanisms for diseases and disease-related traits.

Coupling of metabolomics and exome sequencing reveals graded effects of rare damaging heterozygous variants on gene function and resulting traits and diseases

“…Comparison of our results to those from published studies that focused on rare variant aggregation testing of metabolite levels [14][15][16][17][18][19][20]24 (Methods) showed that 32 of the 73 identified unique genes (44%) had not been reported as significant in any of these studies. Moreover, 115 of all 192 detected gene-metabolite associations (60%) were novel (Supplementary Table 4).…”

“…We compared our significant findings to the significant findings from eight published genetic studies of the plasma/serum or urine metabolome that focused on rare exonic variant aggregation testing and used sequencing and high-throughput metabolomics data [14][15][16][17][18][19][20]24 . We first assessed whether the genes identified in our study were reported as associated with any metabolite in any of the seven studies at their respective multiple-testing corrected significance threshold, after having mapped all gene names to their current version in Ensembl version 109 using https://www.ensembl.org/biomart/martview.…”

“…Gene-based aggregation testing of rare, putatively damaging variants in population studies can address this challenge. Previously, such studies have focused almost exclusively on the circulating metabolome [14][15][16][17][18][19][20] . We have recently shown that GWAS of paired plasma and urine metabolomes not only reveal many more associations, but also enable specific insights into renal metabolite handling 2 .…”

VAMS-Based Blood Capillary Sampling for Mass Spectrometry-Based Human Metabolomics Studies

“…In addition, the minimal volume of the sample collected onto VAMS enables longitudinal metabolomic studies and is particularly in line with the 3R’s principle [ 14 ]. The integration of VAMS with conventional mass spectrometry (MS)-based metabolomics approaches is an attractive solution for different applications, ranging from animal studies to human population studies [ 27 , 28 ] and longitudinal studies [ 29 ].…”

Pervasive Influence of Hormonal Contraceptives on the Human Plasma Proteome in a Broad Population Study

“…Some recent work has been published evaluating the impact of age, sex and diet, amongst others, on the human metabolome (Verri Hernandes et al, 2022). Moreover, gene-metabolite associations (König et al, 2022), as well as genetic and metabolomic determinants of disease (Emmert et al, 2021), have been investigated. We performed a general exploratory analysis of the data set to identify relevant factors affecting the plasma proteome and found hormonal contraceptives to be the main factor explaining the variation in a human plasma proteome from European individuals.…”